Liver Targeting Albumin-Coated Silybin-Phospholipid Particles Prepared by Nab™ Technology for Improving Treatment Effect of Acute Liver Damage in Intravenous Administration

  • 134 Accesses


In this study, a novel human serum albumin nanoparticle loading silybin-phospholipid complex (SLNPs) was developed for liver targeting after intravenous administration. The preparation of the drug delivery system consisted of two steps; initially, a silybin-phospholipid complex (SLC) was produced to improve the lipophilicity of SLB to then achieve enhanced encapsulation of SLB in albumin nanoparticles. FT-IR and XRD analysis confirmed the successful formation of SLC. The complex ratio of SLC in the first step was 99.6%. The encapsulation efficiency and drug loading of SLNPs in the second step were 96.2% and 5.6%, respectively. SLNPs were spherical and well-dispersed, with a zeta potential of approximately − 10 mV, and a mean particle size around 200 nm. An in vivo tissue distribution experiment and a pharmacodynamic experiment showed that, compared with SLB solution, SLNPs had an improved SLB accumulation in the liver. The hepatoprotective effect of SLNPs on CCl4-induced acute liver damage was evaluated. CCl4-damaged mice showed an increased enzymatic activity of ALT and AST; however, enzyme levels returned to near-normal levels in high-dose SLNP-treated mice. As SLNPs combine the enhanced oil solubility of SLC and the passive targeting of albumin nanoparticles, they possess great potential for the treatment of acute liver damage.

This is a preview of subscription content, log in to check access.

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9


  1. 1.

    Shen B, Chen H, Shen C, Xu P, Li J, Shen G, et al. Hepatoprotective effects of lignans extract from Herpetospermum caudigerum against CCl4-induced acute liver injury in mice. J Ethnopharmacol. 2015;164:46–52.

  2. 2.

    Federico A, Dallio M, Loguercio C. Silymarin/silybin and chronic liver disease: a marriage of many years. Molecules. 2017;22(2).

  3. 3.

    Loguercio C, Festi D. Silybin and the liver: from basic research to clinical practice. World J Gastroenterol. 2011;17(18):2288–301.

  4. 4.

    Pradhan SC, Girish C. Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. Indian J Med Res. 2006;124(5):491–504.

  5. 5.

    Xu P, Zhou H, Li Y-Z, Yuan Z-W, Liu C-X, Liu L, et al. Baicalein enhances the oral bioavailability and hepatoprotective effects of silybin through the inhibition of efflux transporters BCRP and MRP2. Front Pharmacol. 2018;9.

  6. 6.

    Yuan Z-W, Li Y-Z, Liu Z-Q, Feng S-l, Zhou H, Liu C-X, et al. Role of tangeretin as a potential bioavailability enhancer for silybin: pharmacokinetic and pharmacological studies. Pharmacol Res. 2018;128:153–66.

  7. 7.

    Zhao X, Deng Y, Zhang Y, Zu Y, Lian B, Wu M, et al. Silymarin nanoparticles through emulsion solvent evaporation method for oral delivery with high antioxidant activities, bioavailability, and absorption in the liver. RSC Adv. 2016;6(95):93137–46.

  8. 8.

    Guan X-L, Zhao S-Z, Hou R-J, Yang S-H, Zhang Q-L, Yin S-L, et al. Pharmacokinetics of silybin nanoparticles in mice bearing SKOV-3 human ovarian carcinoma xenocraft. Int J Clin Exp Med. 2015;8(10):17406–17.

  9. 9.

    Wu J-W, Lin L-C, Hung S-C, Chi C-W, Tsai T-H. Analysis of silibinin in rat plasma and bile for hepatobiliary excretion and oral bioavailability application. J Pharm Biomed Anal. 2007;45(4):635–41.

  10. 10.

    Maryana W, Rachmawati H, Mudhakir D. Formation of phytosome containing silymarin using thin layer-hydration technique aimed for oral delivery ☆. Mater Today Proc. 2016;3(3):855–66.

  11. 11.

    Angelico R, Ceglie A, Sacco P, Colafemmina G, Ripoli M, Mangia A. Phyto-liposomes as nanoshuttles for water-insoluble silybin-phospholipid complex. Int J Pharm. 2014;471(1–2):173–81.

  12. 12.

    Mahira S, Kommineni N, Husain GM, Khan W. Cabazitaxel and silibinin co-encapsulated cationic liposomes for CD44 targeted delivery: a new insight into nanomedicine based combinational chemotherapy for prostate cancer. Biomed Pharmacother.

  13. 13.

    Yousaf AM, Malik UR, Shahzad Y, Mahmood T, Hussain T. Silymarin-laden PVP-PEG polymeric composite for enhanced aqueous solubility and dissolution rate: preparation and in vitro characterization. J Pharm Anal.

  14. 14.

    Calligaris S, Comuzzo P, Bot F, Lippe G, Zironi R, Anese M, et al. Nanoemulsions as delivery systems of hydrophobic silybin from silymarin extract: effect of oil type on silybin solubility, in vitro bioaccessibility and stability. LWT Food Sci Technol. 2015;63(1):77–84.

  15. 15.

    Hădărugă DI, Hădărugă NG, Bandur GN, Isengard HD. Water content of flavonoid/cyclodextrin nanoparticles: relationship with the structural descriptors of biologically active compounds. Food Chem. 2012;132(4):1651–9.

  16. 16.

    Nguyen MH, Yu H, Dong B, Hadinoto K. A supersaturating delivery system of silibinin exhibiting high payload achieved by amorphous nano-complexation with chitosan. Eur J Pharm Sci. 2016;89:163–71.

  17. 17.

    Qiu-Hong LI, Yang L, Ying WU, Yue GE, Tian-Ying LI. Pharmacokinetics and tissue distribution in rats by injection use of silybin meglumine salt. Nformaon on Radonal Hn Mdn. 2012.

  18. 18.

    Kidd P, Head K. A review of the bioavailability and clinical efficacy of milk thistle phytosome: a silybin-phosphatidylcholine complex (Siliphos). Altern Med Rev. 2005;10(3):193–203.

  19. 19.

    Song Y, Zhuang J, Xiao Y, Ping Q. Preparation and properties of a silybin-phospholipid complex. Pharmazie. 2008;63(1):35–42.

  20. 20.

    Kratz F. Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Control Release. 2008;132(3):171–83.

  21. 21.

    Min SY, Byeon HJ, Lee C, Seo J, Lee ES, Shin BS, et al. Facile one-pot formulation of TRAIL-embedded paclitaxel-bound albumin nanoparticles for the treatment of pancreatic cancer. Int J Pharm. 2015;494(1):506–15.

  22. 22.

    Desai N, Desai N. Nanoparticle albumin bound (nab) technology: targeting tumor through the endothelial gp60 receptor and SPARC. Nanomed Nanotechnol Biol Med. 2007;3(4):339.

  23. 23.

    Gradishar WJ. Albumin-bound paclitaxel: a next-generation taxane. Expert Opin Pharmacother. 2016;7(8):1041.

  24. 24.

    He X, Xiang N, Zhang J, Zhou J, Fu Y, Gong T, et al. Encapsulation of teniposide into albumin nanoparticles with greatly lowered toxicity and enhanced antitumor activity. Int J Pharm. 2015;487(1–2):250–9.

  25. 25.

    Li FQ, Su H, Wang J, Liu JY, Zhu QG, Fei YB, et al. Preparation and characterization of sodium ferulate entrapped bovine serum albumin nanoparticles for liver targeting. Int J Pharm. 2008;349(1):274–82.

  26. 26.

    Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev. 2001;53(2):283–318.

  27. 27.

    Ishida T, Masuda K, Ichikawa T, Ichihara M, Irimura K, Kiwada H. Accelerated clearance of a second injection of PEGylated liposomes in mice. Int J Pharm. 2003;255(1):167–74.

  28. 28.

    Yang YF, Xie XY, Yang Y, Hui Z, Mei XG. A review on the influences of size and surface charge of liposome on its targeted drug delivery in vivo. Acta Pharm Sin. 2013;48(11):1644–50.

  29. 29.

    Lu Y, Li Y, Wu W. Injected nanocrystals for targeted drug delivery. Acta Pharm Sin B. 2016;6(2):106–13.

  30. 30.

    Müller RH, Gohla S, Keckacd CM. State of the art of nanocrystals – special features, production, nanotoxicology aspects and intracellular delivery. Eur J Pharm Biopharm. 2011;78(1):1–9.

  31. 31.

    Wu H, Long X, Yuan F, Chen L, Pan S, Liu Y, et al. Combined use of phospholipid complexes and self-emulsifying microemulsions for improving the oral absorption of a BCS class IV compound, baicalin. Acta Pharm Sin B. 2014;4(3):217–26.

  32. 32.

    Ma H, Chen H, Sun L, Tong L, Zhang T. Improving permeability and oral absorption of mangiferin by phospholipid complexation. Fitoterapia. 2014;93(3):54–61.

  33. 33.

    Jia L, Zhang D, Li Z, Duan C, Wang Y, Feng F, et al. Nanostructured lipid carriers for parenteral delivery of silybin: biodistribution and pharmacokinetic studies. Colloids Surf B Biointerfaces. 2010;80(2):213–8.

  34. 34.

    Hu Y, Li Z, Shi W, Yin Y, Mei H, Wang H, et al. Early diagnosis of cerebral thrombosis by EGFP-EGF1 protein conjugated ferroferric oxide magnetic nanoparticles. J Biomater Appl. 2019;33:1195–201.

  35. 35.

    Zhang K, Gu L, Chen J, Zhang Y, Jiang Y, Zhao L, et al. Preparation and evaluation of kaempferol–phospholipid complex for pharmacokinetics and bioavailability in SD rats. J Pharm Biomed Anal. 2015;114:168–75.

  36. 36.

    Cengiz M, Kutlu HM, Burukoglu DD, Ayhancı A. A comparative study on the therapeutic effects of silymarin and silymarin-loaded solid lipid nanoparticles on D-GaIN/TNF-α-induced liver damage in Balb/c mice. Food Chem Toxicol. 2015;77:93–100.

  37. 37.

    Ishihara T, Takahashi M, Higaki M, Takenaga M, Mizushima T, Mizushima Y. Prolonging the in vivo residence time of prostaglandin E 1 with biodegradable nanoparticles. Pharm Res. 2008;25(7):1686–95.

  38. 38.

    Guan T, Miao Y, Xu L, Yang S, Wang J, He H, et al. Injectable nimodipine-loaded nanoliposomes: preparation, lyophilization and characteristics. Int J Pharm. 2011;410(1):180–7.

  39. 39.

    Hawkins MJ, Patrick SS, Neil D. Protein nanoparticles as drug carriers in clinical medicine. Adv Drug Deliv Rev. 2008;60(8):876–85.

  40. 40.

    Bracht EV, Raavé R, Perevyazko IY, Versteeg EM, Hafmans TG, Schubert US, et al. Biodistribution of size-selected lyophilisomes in mice. Eur J Pharm Biopharm. 2015;94:141–51.

  41. 41.

    Özerkan D, Özsoy N, Akbulut KG, Güney S, Öztürk G. The protective effect of vitamin D against carbon tetrachloride damage to the rat liver. Biotech Histochem. 2017;92(2):1–11.

  42. 42.

    Xiaoping H, Xiao W, Yinghui L, Luli X, Junsheng L, Yong D. Protection effect of kallistatin on carbon tetrachloride-induced liver fibrosis in rats via antioxidative stress. PLoS One. 2014;9(2):e88498.

  43. 43.

    Venema FR, Weringa WD. The interactions of phospholipid vesicles with some anti-inflammatory agents. J Colloid Interface Sci. 1988;125(2):484–92.

  44. 44.

    Kim TH, Hai HJ, Yu SY, Chan WP, Tak KK, Lee S, et al. Preparation and characterization of water-soluble albumin-bound curcumin nanoparticles with improved antitumor activity. Int J Pharm. 2011;403(1–2):285–91.

  45. 45.

    Paál K, Müller J, Hegedûs L. High affinity binding of paclitaxel to human serum albumin. Eur J Biochem. 2010;268(7):2187–91.

  46. 46.

    Bertucci C, It LU, Domenici E. Reversible and covalent binding of drugs to human serum albumin: methodological approaches and physiological relevance. Curr Med Chem. 2002;9(15).

  47. 47.

    Mahmoodzadeh Y, Mazani M, Rezagholizadeh L. Hepatoprotective effect of methanolic Tanacetum parthenium extract on CCl4-induced liver damage in rats. Toxicol Rep. 2017;4:455–62.

  48. 48.

    Flaig TW, Gustafson DL, Su LJ, Zirrolli JA, Crighton F, Harrison GS, et al. A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients. Investig New Drugs. 2007;25(2):139–46.

  49. 49.

    Wellington K, Jarvis B. Silymarin: a review of its clinical properties in the management of hepatic disorders. Biodrugs. 2001;15(7):465–89.

  50. 50.

    Fraschini F, Demartini G, Esposti D. Pharmacology of silymarin. Clin Drug Investig. 2002;22(1):51–65.

Download references


Amanda Pearce is sincerely thanked for correcting the manuscript. The authors alone are responsible for the content and writing of this article.

Author information

Correspondence to Haibing He.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lu, C., Li, X., Liang, X. et al. Liver Targeting Albumin-Coated Silybin-Phospholipid Particles Prepared by Nab™ Technology for Improving Treatment Effect of Acute Liver Damage in Intravenous Administration. AAPS PharmSciTech 20, 293 (2019).

Download citation


  • acute liver damage
  • silybin-phospholipid complex
  • SLNPs
  • liver targeting
  • intravenous administration